Imidazo(5,1-f)triazinones

ABSTRACT

1. A A COMPOUND OF THE FORMULA I:   2-(R1-N(-R2)-),3-R3,4-(O=),5-R4,7-R5-IMIDAZO(5,1-F)   TRIAZINE   OR A PHYSIOLOGICALLY ACCEPTABLE SALT THEREOF WHEREIN R2 AND R3 MAY BE THE SAME OR DIFFERENT AND EACH REPRESENTS A HYDROGEN ATOM OR A STRAIGHT OR BRANCHED CHAIN ALKYL OR ALKENYL RADICAL CONTAINING FROM 1 TO 6 CARBON ATOMS OR SUCH A RADICAL SUBSTITUTED BY AT LEAST ONE PHENYL GROUP, R1 IS AS DEFINED FOR R2 AND R3 OR A C1-C6 ALKANOLY GROUP, AND R4 AND R5 ARE AS DEFINED FOR R2 AND R3 OR A C3-C7 CYCLOALKYL, OR PHENYL GROUP.

" United States Patent Offlce 3,840,537 Patented Oct. 8, 1974 U.S. Cl.260-2495 21 Claims ABSTRACT OF THE DISCLOSURE Compounds of the generalformula I:

and physiologically acceptable salts thereof, wherein R R R R and R maybe the same or diflerent and each represent a hydrogen atom or astraight or branched chain alkyl or alkenyl radical containing from 1 to6 carbon atoms, which may optionally be substituted by one or more arylgroups. R, in addition may represent an acyl (C -C group and R and R mayindependently represent a cycloalkyl, arylalkyl or aryl group. Thesecompounds act as spasmolytics and phosphodiesterase inhibitors.

This invention relates to certain heterocyclic compounds havingpharmacological activity and to processes for the preparation thereof aswell as pharmaceutical compositions containing them.

We have found that certain imidazo [5,1-f] triazinones act asspasmolytics and phosphodiesterase inhibitors and have cardiotonic anddiuretic properties. They are therefore particularly useful in thetreatment of diseases involving constriction of bronchial muscle, forexample asthma and bronchitis and also for the treatment of pulmonaryoedema and congestive heart failure. The compounds may also be useful inthe treatment of skin diseases, for example psoriasis.

The present invention therefore provides compounds of the generalformula I:

and physiologically acceptable salts thereof, wherein R R R R and R maybe the same or different and each represent a hydrogen atom or astraight or branched chain alkyl or alkenyl radical containing from 1 to6 carbon atoms, which may optionally be substituted by one or more arylgroups. R in addition may represent an acyl (C -C group and R and R mayindependently represent a cycloalkyl, arylalkyl or aryl group.

Compounds of the general formulae may exist in several tautomeric formsand these are included within the scope of the invention.

Preferred compounds are those in which R represents hydrogen or acyl (CR represents hydrogen, R represents hydrogen or lower alkyl (C Rrepresents hydrogen or lower alkyl (C and R represents lower alkyl (Ccycloalkyl (C aryl or arylalkyl (C alkyl). In a particular class ofcompounds R R and R all represent hydrogen. Preferred compounds arethose whose preparation is described in the Examples.

The activity of these compounds is demonstrated by their action in theguinea pig in reducing bronchospasm induced by spasmogens such ashistamine, S-hydroxytryptamine and acetylcholine according to standardtest procedures. [Konzett, H, and Rossler, R. (1940). Versuchsanordungzu Untersuchungen an der Bronchial musculatur. Arc. exp. Patho.PharmakoL, 195, 71-74]. For instance, 2-amino 5 methyl-7-propylimidazo[5,1-f]-astriazin-4(3H)one, hydrochloride is more active than standardnon-adrenergic bronchodilators, such as choline theophyllinate. Thiseffect is even more apparent in preparations of the isolated trachea ofthe guinea pig, in response to challenge with acetylcholine. The resultsof these tests are shown in the Table below:

guinea pig trachea.

The compounds of the invention are inhibitors of the enzymephosphodiesterase. For instance, at a concentration of 5 10 M, 2amino-5-methyl-7-propyl-imidazo [5,l-f] -as-triazin-4(3-H)-one,hydrochloride is 8 times more potent than choline theophyllinate ininhibiting the degradative action of this enzyme on cyclic adenosinemonophosphate, a humoral agent important in bronchodilator mechanisms.

The compounds according to the invention may be formulated for use inhuman and veterinary medicine for therapeutic and prophylactic purposes.They will in general be used in the form of their physiologicallyacceptable salts. Preferred salts include the hydrochloride, sulphate,maleate, tartrate,. etc. Such compounds may be presented for use in theconventional manner with the aid of carriers or excipients andformulating agents as required, and with or without supplementarymedicinal agents.

The compositions may include solid and liquid preparations for oral use,suppositories or injections, or forms suitable for administration byinhalation. Oral administration is most convenient in the form oftablets. Injections may be formulated with the aid of physiologicallyacceptable carriers and agents as solutions, suspensions or as dryproducts for reconstitution before use. For administration by inhalationthe compounds according to the invention are conveniently delievered inthe form of an aerosol spray presentation from pressurised packs or anebuliser. In the case of a pressurised aerosol the dosage unit may bedetermined by providing a valve to deliver a metered amount. A typicaldose for treating asthma in humans is from 1-200 mg. depending on theage, weight and condition of the patient and the route ofadministration.

The compounds according to the invention may be formulated incombination with compounds such as salbutamol and isoprenaline that havestimulant activity at B adrenoreceptors. These combinations, asexemplified by Z-amino-S-methyl-7-propyl-imidazo[5,l-f] as triazin-4(3H)-one and salbutamol, are more effective than the sum of the twoactive ingredients given separately and the compounds are thereforesynergistic. The preceding combination was about 2.5 times more potentthan pred-icted from the individual dose response curves. The provisionof therapeutic compositions comprising as active ingredients, a compoundaccording to the invention and a p-adrenoreceptor stimulant, inparticular salbutamoi, represents an aspect of the present invention.

The compounds according to the invention may be prepared by a number ofprocesses. In one of these an amino guanidine II or an appropriate salt,e.g. hydrogen carbonate, is condensed with an a-ketoester III to yieldthe as-triazinone ester -IV. The N-benzyl derivative V of the lastmentioned compound is then converted into an amine VII, for example byCurtius degradation via the corresponding hydrazine VI or by Hofimandegradation of the amide. The amine VII may then be acylated byconventional procedures, e.g. using acid halides or anhydrides to givethe intermediate VIII. This amide is then cyclised by refluxing with acyclodehydrating agent e.g. phosphorus oxychloride, with concomitantremoval of the protecting group. The sequence is shown in the chart.

CHART NH: AlkOOC R4 COOAlk RIRZN 11 In 0 R4 HMGOOAK N R R N- i 2 \N/ IV114 I COOAlk a N1 mam-Ka dnirn v t Ijfiq CONHNHQ RlR2N dnirn VI if NHz NRrRzN \N/ damn VII 9 N LK NH :0R5

damn

HN Nnoom R RzN N vrrr VIIIa *In the Provisional Specification we hadsuggested that the protective benzyl group was positioned on the oxygenatom at 0-5. We now know that this is incorrect and that reaction hadoccurred with one of the several other tautomers of the triazinone (IV)to give the N-2 benzyl compounds (V) shown. This minor structuralcorrection does not alter the designed function of the benzylation whichis to prevent premature cyclisation on to the triazine ring. The courseof the synthetic process is unaffected although the nomenclature of theintermediate in some of the examples difiers from that used in theProvision Specification.

lPPA

Alternatively the final step can be carried out in two stages in whichthe benzyl group is first removed e.g. b'y hydrogenolysis in thepresence of noble metal catalyst, and the triazinone VIIIa is thenconverted into IX by heating with a cyclodehydrating compound e.g.polyphosphoric acid.

Compounds of the invention in which R /R are other than hydrogen arebest prepared by a related process in which the keto ester III is firstcondensed with thiosemicarbazide to give the thione X. The last isconverted into the alkylthioether XI with an alkyl halide and a basesuch as sodium hydroxide in the presence of a solvent, and the N-benzylderivative XII is formed as before. The mercapto group can then bedisplaced by heating with an amine vR R NH to give the intermediate V ofthe general synthesis:

Hm OaAlk l IT/YKC ozAlk l CHaPh XII Compounds of the invention where Ris other than hydrogen may be prepared from compounds of general formulaVIII and conventional alkylating agents R X, where X may be for example,halogen or tosylate in the presence of a strong base, for example sodiumhydride and in a suitable solvent e.g. N,N-dimethylformamide.

The resulting imine XIII then undergoes hydrogenolysis andcyclodehydration as before.

RzN N (iHiPh The following Examples illustrate the invention:

'EXAMPLE 1 3-Amino-2,S-dihydrQ-a-methyI-S-oxo-as-triazine-6- aceticacid, ethyl ester XIII EXAMPLE 23-Amino-2-benzyl-2,S-dihydro-a-methyl-5-oxo-asttriazine-6-acetic acid,ethyl ester A mixture of 3 amino 2,5-dihydro-a-methyl-5-oxo-astriazine-6-acetic acid, ethyl ester (2.0 g.), benzyl chloride (1.3 g.),potassium carbonate (1.6 g.) and sodium iodide (0.5 g.) in butanone (100ml.) was refluxed with stirring for 2 days. The mixture was filtered,and the filtrate was evaporated under reduced pressure to yield a yellowoil which was dissolved in ethyl acetate and washed with water. Theethyl acetate solution was dried (MgSO and evaporated to give a yellowoil, which on trituration with a mixture of ether, light petroleum (b.p.40-60") and ethyl acetate gave a white solid, m.p. 14l-143.Recrystallisation from ethyl acetate yielded white microcrystals, m.p.l51152.

By a similar procedure 3-amino-2,S-dihydro-S-oxo-astriazine-6-aceticacid, ethyl ester was converted into 3- amino-2-benzyl-2,5 dihydro 5oxo-as-triazine-G-acetic acid, ethyl ester, m.p. 188 (from ethylacetate) and 3-amino 2,5-dihydro 5-oxo-a-propyl as triazine-6- aceticacid, ethyl ester was converted into 3-amino-2-benzyl-2,5-dihydro 5oxo-a-propyl-as-triazine-6-acetic acid, ethyl ester, m.p. 128129 (fromethyl acetate).

EXAMPLE 33-Amino-2-benzyl-2,5-dihydro-a-methyl-5-oxoas-triazine-6-acetic acid,hydrazide 3-Amino 2 benzyl2,5-dihydro-a-methyl-5-oxo-astriazine-6-acetic acid, ethyl ester (7.5g.) in methanol (100 ml.) and hydrazine hydrate (100 ml.) was allowed tostand for 3 days. Evaporation of the solvents under reduced pressure andcrystallisation of the residue from methanol yielded white needles, m.p.246 C.

By a similar procedure 3-amino-2-benzyl-2,S-dihydro-5-oxo-as-triazine-6-acetic acid, ethyl ester was converted into3-amino-2-benzyl-2,S-dihydro 5 oxo as triazine- 6-acetic acid,hydrazide, m.p. 249-251 (dec.) (from ethanol) and 3-amino-2-benzyl 2,5dihydro 5 oxoa-propyl as triazine 6 acetic acid, ethyl ester wasconverted into 3-amino 2 benzyl-2,5-dihydro 5 oxo-apropyl-as-triazine 6acetic acid, hydrazide, m.p. 238- 239.

EXAMPLE 4 3-Amino-2-benzyl-2,5-dihydro-a-methyl-5-oxo as-6-acetic acidamide A solution of 3-amino-2-benzyl-2,5-dihydro-a-methyl-5-oxo-as-triazine-6-acetic acid, ethyl ester (5 g.) in methanol (120ml.) and aqueous ammonia (d 0.88, 360 ml.) was allowed to stand at roomtemperature for 5 days. The amide separated as a white solid, m.p.272274 (2.6 g.). Concentration of the filtrate to ca. 150 ml. afiorded asecond crop, m.p. 268269 (0.75 g.). Recrystallisation from aqueousdimethylformamide (1:2) gave material m.p. 271-273".

EXAMPLE 5 3-Amino-6- l-aminoethyl -2-benzyl-as-triazine- 5(2H)-0neMethod A A solution of 3-amino 2 benzyl 2,5-dihydro-a-methyl-5-oxo astriazine 6 acetic acid, hydrazide (80 g.) in concentrated hydrochloricacid (52.8 ml.) and water (800 ml.) was cooled to 8 and a solution ofsodium nitrite (20.46 g.) in water (400 ml.) was added dropwise over 20minutes keeping the temperature below 10. The mixture was stirred below10 for 45 minutes, concentrated hydrochloric acid (80 ml.) was added andthe temperature then raised to 60 whereupon the solid dissolved. Thesolution was maintained at 60 for 1 hour then cooled to 10 and sodiumhydroxide (53.5 g.) was added over minutes keeping the temperature belowThe diamine separated as a White solid, m.p. 244246 (48-54 g.).

By a similar procedure 3-amino-2-benzyl-2,S-dihydro- 5-oxo-as-triazine 6acetic acid, hydrazide was converted into 3-amino-6-aminomethyl 2 benzylas triazine- 5 (2H)-one, m.p. 195.5-197.5 and 3-amino-2-benzyl-2,5-dihydro 5 oxo-a-propyl-as-triazine-6-acetic acid, hydrazide wasconverted into 3-amino-6-(l-aminobutyl)-2- benzyl-as-triazin-S-(ZH)-one,m.p. 216-218 (from ethanol).

Method B 3-Amino 2 benzyl- 2,5 dihydro-a-metl'iyl-5-oxo-astriazine-6-acetic acid, amide (0.68 g.) was added to a stirred ice coldsolution of sodium of sodium hypobromite prepared by adding bromine(0.24 ml.) to an ice cold solution of sodium hydroxide (0.72 g.) inwater (6 ml.). The solid dissolved after 20 minutes and the solution wasstirred for 4 hours at room temperature. Eifervescence occurred onacidification, and after basification with sodium hydroxide and cooling,the diamine crystallised out, m.p. 247248 (0.3 g.).

EXAMPLE 6 N-[ 1- (3-Amino-2-benzyl-2,S-dihydro-S-oxo-astriazin-6-yl)ethyl] butyramide Method A Butyric anhydride (57.5 ml.) wasadded to a stirred suspension of 3-amino-6-(l-aminoethyl)-2-benzylas-triazin-5(2H)-one g.) in dioxan (800 ml.) at room temperature.Stirring was continued for 2 hours. The solution was then diluted withether and the product collected m.p. 174 (103 g.). Recrystallisationfrom methanol (400 ml.) and water 800 ml.) gave the butyramide as whitecrystals, m.p. 193--194 (88 g.).

By a similar procedure 3-amino-6-(1-aminomethyl)-2- benzyl-as-triazin-S(2H) one gave N-[l-(3-amino-2- benzyl-2,5-dihydro5-oxo-as-triazin-6-yl)methylJbutyramide m.p. -498 (from ethanol).

Method B Butyryl chloride (3.3 ml.) was added to a stirred suspension of3-amino-6-(l-aminoethyl)-2-benzyl-as-triazin- 5(2H)-one (7.0 g.) inpyridine (70 ml.) at room temperature. The solution was stirred for 17/2 hours and diluted with ether (400 ml.) to percipitate the butyramide.This was collected, taken up in methanol and water was added until thesolution was turbid. The butyramide separated as a white solid, m.p.189l92 (5.55 g.).

The following compounds were prepared from 3-arnino- G-(I-aminoethyU-Zbenzyl as-triazin-S (2H)-one by a similar procedure.N-[1-(3-amino-2-benzyl-2,S-dihydro-5-oxo-as-triazin-6-yl)ethyl]isovaleramide m.p. 213.6; N-[1-(3-amino2-beuzyl 2,5-dihydro-S-oxo-as-triazin- 6-yl)ethyl]acetamide m.p.2l6-219; N-[1-(3-amino-2- benzyl-2,5 dihydro-S-oxoas-triazin-G-yl)ethyl]valeramide m.p. 191.

Method C A solution of3-amino-6-(l-aminoethyl)-2-benzyl-astriazin-5(2H)-one (6.0 g.) inbutyric acid (30 ml.) was boiled under reflux for 4 hours. Butyric acidwas removed by distillation under reduced pressure and the residualblack oil was triturated with dry ether to give a buflf solid. Thismaterial was absorbed onto silica gel, and eluted with methanol ethylacetate (1:9) to give the butyramide (2.2 g.), m.p. 192-l94.

EXAMPLE 7 N-[ 1- (3-Amino-2,5-dihydro-5-oxo-as-triazin-6- yl) ethyl]butyramide N-[l-(3-Amino 2benzyl-2,S-dihydro-S-oxo-as-triazin-6-yl)ethyl]butyramide (40 g.) in 2Nhydrochloric acid (200 ml.) was hydrogenated over 10% palladium oncharcoal (4 g.) at room temperature. Hydrogen uptake was complete after1.75 hours. The catalyst was removed by filtration through Hyflo and thefiltrate was neutralised with sodium carbonate to precipitate thetriazinone as a white solid, m.p. 312 (dec.) (23.1g.).'Recrystallisation from dimethylformamide gave material m.p. 316.5(dec.).

By a similar procedureN-[l-(3-amino-2-benzyl-2,5-dihydro--oxo-as-triazin-6-yl)ethylJisovaleramidegave N- [1-(3-amino-2,5-dihydro 5 oxo-as-triazin-6-yl)ethyl]isovaleramide, m.p. 271; -N-[1-(3-amino-2-benzyl-2,5-dihydro-5-oxo-as-triazin-6-yl)methyl]butyramide gave N-[1-(3-amino-2,5-dihydro 5 oxo-as-triazin--yl)methyl] butyramide m.p.300.

EXAMPLE 8 Z-Amino-S-methyl-7-propyl-imidazo[5,1-f] as-triazin-4(3H)-one, hydrochloride Method A N-[1-(3-Arnino2,5-dihydro 5oxo-as-triazin-G-yl) ethyl]butyramide g.) was stirred withpolyphosphoric acid (70 g.) at 100 and the temperature was then raisedto 140 for 1 hour. The hot yellow solution was poured into water (500ml.) and neutralised with sodium carbonate to precipitate theimidazo-triazinone as a white solid, m.p. l254 (8.4 g.). The base wastaken up in ethanol ml.) and 10% ethanolic hydrogen chloride (25 ml.)was added to precipitate the hydrochloride, m.p. 282-285 (8.25 g.).Recrystallisation from water. (6 ml.) and ethanol (50 ml.) gave materialm.p. 285-289 (6.3 g.).

By a similar procedure N-[1-(3-amino-2,5-dihydro-5-oxo-as-triazin-6-yl)ethyl]isovaleramide gave 2-amino-7- isobutyl-Smethyl-imidazo[5,1-f] -as-triazin-4(3H)-one, m.p. 25l252 (dec.) (fromethyl acetate); N-[1-(3- amino-2,5-dihydro 5-oxo-as-triazin-6yl)methyl]butyramide gave 2 amino-7-propyl-imidazo[5,1-f1-as-triazin-4(3H)-one hydrochloride m.p. 23l232 (from ethanolether) N- 1-3-amino-2,5-dihydro-5-oxo-as-triazin-6-yl) valeryl]acetamide gave2-amino-7-methyl-5-propyl-imidazo[5,l-f]-as-triazin-4(3H) one,hydrochloride, m.p. 270-274 with decomposition.N-[1-(3-amino-2,5-dihydro-S oxo-as-triazin 6-yl)ethyl]cyclopentanecarboxamide gave 2-amino-5methyl-7-cyclopentyl-imidazo- [5,1-f]-as-triazin-4(3H)-one, m.p. 299302.N-[1-(3- amino-2,5-dihydro S-oxo-as-triazin 6-yl)ethyl]phenylacetamidegave 2-amino 7-benzyl-5-methyl-imidazo- [5,1-f]-as-triazin-4(3H)-one,m.p. 270.5-271.5 with decomposition.N-[1-(3-arnino-2,S-dihydro-S-oxo-as-triazin- 6-yl)ethyl]benzamide gave2-amino-5-methyl-7-phenylimidazo[5,l-f]-as-triazin-4(3H)-one,hydrochloride, m.p. 315-317 with decomposition.N-[1-(3-amino-2,5-dihydro-5-oxo-as-triazin-6-yl)ethyl] -3,3dimcthylbutyramide gave2-amino-7-neopentyl-S-methylimidazo[5,1-f1-as-triazin-4(3H)-one,hydrochloride, m.p. 261-263". N-[1-(3- amino-2,5-dihydro 5oxo-as-triazin-G-yl)ethyl]hydrocinnamide gave2-amino-5-methyl7-phenethylimidazo- [5,1-f]-as-triazin-4(3H)-one,hydrochloride, m.p. 271- 274.5".

Method B N-[1-(3-amino Z-benzyl 2,5dihydro-S-oxo-as-triazin-6-yl)ethyl]butyramide (2.2 g.) was dissolved inphosphorus oxychloride (50 ml.) and the solution boiled under reflux for30 minutes. The solution was cooled, poured onto ice and concentratedhydrochloric acid and adjusted to 6H 7 by the addition of solid sodiumbicarbonate. The mixture was extracted with ethyl acetate and theextract was dried and concentrated. The residue in ethyl acetate wasadsorbed onto silica gel (50 g.). Elution with ethyl acetate gave theimidazo[5,1-f]-astriazine as an off-white solid, m.p. 259-261. Thehydrochloride salt had m.p. 277280 (from ethanol).

By a similar procedureN-[l-(3-amino-2-benzyl-2,5-dihydro-S-oxo-as-triazin 6 yl)ethyl]acetamidegave 2- amino-5,7-dimethyl-imidazo[5,1-f] as triazin-4(3H)- one, m.p.380-384 (dec.); N-[1-(3-amino-2-benzyl-2,5-dihydro-5-oxo-as-triazin-6-yl)ethyl]valeramide gave 2- 8 amino-7-butyl 5methyl-imidazo[5,1-f] -as-triazin-4- (3H)-one, m.p. 214215.

EXAMPLE 9 N- 3,4-Dihydro-S-methyl-4 oxo-7-propyl-imidazo [5 l-f 1-as-triazin-2-yl acetamide, hydrochloride Method A A solution of2-amino-5-methyl-7-propyl-imidazo- [5,1-f]-as-triazin-4(3H)-one (1.4 g.)in glacial acetic acid (12 ml.) and acetic auhydride (12 ml.) was heatedat for 4 hours then poured onto ice. The solution was neutralised withsodium carbonate and then extracted with ethyl acetate (4X ml.). Removalof the solvent gave the acetamide as a white powder m.p. 201.8 (1.59g.). Three recrystallisations from ethyl acetate/ light petroleum (b.p.60-80") gave material m.p. 220- 221.

The base (1.0 g.) was taken up in ethanol (15 ml.) and treated withethereal hydrogen chloride to precipitate the hydrochloride, m.p.248-251. Two recrystallisations from ethanol-ether gave material, m.p.267- 269.

Method B A solution of 2-amino5-methyl-7-propyl-imidazo-[5,1-f]-as-triazin-4(3H)-one, hydrochloride (0.7 g.) andmethanesulphonyl chloride (0.5 ml.) in glacial acetic acid (25 ml.) wasboiled under reflux for 17 hours. Solvent was removed and the residuetreated with sodium carbonate solution. The acetamide was collected(0.59 g.) and recrystallisation from ethyl acetate petroleum ether gavematerial, m.p. 221223.

By a similar procedure2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazin-4(3H)-onehydrochloride was converted intoN-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)butyramide, hydrochloride, m.p. 237239 (from ethanol ethyl acetate).

EXAMPLE 10 2-Amino-3,5-dimethyl-7-propyl-imidazo[5,1-f]-astriazin-4 3H)-one, hydrochloride (a) N- l- (2-Benzyl-2,5-dihydro-3-imino-4-methyl-5-oxo-astriazin-6-yl ethyl] butyramide, hydrochloride A solution ofN-[1-(3-amino-2-benzyl-2,S-dihydro-5- oxo-as-triazin-6-yl)ethyl]butyramide (0.5 g.), sodium hydride (60% dispersion in oil, 0.6 g.) andmethyl iodide (0.28 g.) in dimethylformamide (5 ml.) was kept at roomtemperature for 3 days. The solvent was removed by evaporation underreduced pressure and the residue partitioned between ethyl acetate andwater. The organic layer was dried and concentrated and the residuetaken up in ether. Addition of ethereal hydrogen chloride then gave thebutyramide hydrochloride as a lemon-yellow solid (0.4 g.). Tworecrystallisations from methanol and ethyl acetate gave a white solid,m.p. 202203.

(b) N- 1- 3-amino-4,5-dihydro-4-methyl-5-oxo-astriazin-6-yl)ethyl]butyramide N[1-(2-Benzyl-2l,5-dihydro-3-imino 4 methyl-5-oxo-as-triazin-tS-yl)ethyl]butyramide, hydrochloride (2.0 g.) in ethanol(20 ml.) was hydrogenated over 10% palladium on charcoal (1.0 g.).Uptake of hydrogen was complete after 148 ml. had been absorbed. Thecatalyst was removed and the solution concentrated to give a whitesolid, m.p. 224 (1.47 g.). Two recrystallisations from methanol andethyl acetate gave white microcrystals, m.p. 23023l.

(c) 2-Amino-3,S-dimethyl-7-propyl-imidazo [5,1-f1-astriazin-4(3H)-one,hydrochloride The N-[1-(3-amino-4,5-dihydro 4methyl-S-oxo-mstriazin-fi-yl)ethyl]butyramide (0.85 g.) was dissolved inpolyphosphoric acid (9 g.) at 150-160 and the mixture was maintained atthis temperature for 2 hours, then cooled and hydrolysed with water (20mls.). The mixture was adjusted to pH 4-5 by the addition of sodiumcarbonate and a white precipitate separated. This was taken up in ethylacetate and treated with ethereal hydrogen chloride to deposit theimidazo-triazinone hydrochloride as a white powder, m.p. 198 (0.6 g.).Recrystallisation from methanol-ethyl acetate gave white microcrystals,m.p. 198-199.

EXAMPLE 11 Preparation of Intermediate of general formula V (a)Diethyloxalopropionate thiosemicarbazone Thiosemicarbazide (27.3 g.) wassuspended in ethanol (600 ml.) containing formic acid (6 ml.) anddiethyloxalopropionate (60.0 g.) and the mixture was boiled under refluxuntil all the thiosemicarbazide dissolved (2.25 hours). The yellowsolution was concentrated and the residual solid washed with water andrecrystallised twice from ethanol (400 ml.) and water (200 ml.) to givethe thiosemicarbazone as stout needles, m.p. 113.2 (27.4 g.). Twofurther recrystallisations from aqueous ethanol afforded material m.p.114.7".

(b) 2,4-Dihydro-a-methyl--oxo-3-thio-as-triazine-6- acetic acid, ethylester A solution of diethyloxalopropionate thiosemicarbazone (25 g.) andsodium hydroxide (3.65 g.) in ethanol (250 ml.) was boiled under refluxfor 2.5 hours. The solution was filtered and concentrated to a glass.This was taken up in water (100 ml.) and the cloudy solution brought topH 1 by the addition of cone. hydrochloric acid. Theoxo-thio-as-triazine separated as a white solid and was collected andrecrystallised from aqueous ethanol to give material m.p. 149-152" (11.7g.). A further recrystallisation from aqueous ethanol affordedcolourless plates, m.p. ISO-153.

(c) 2,4-Dihydro-a-methyl-3-methylthio-5-oxo-astriazine-6-acetic acid,ether ester Methyl iodide (1.4 ml.) was added to a solution of2,4-dihydro-a-methyl-5-oxo-3-thio-as-triazine 6 acetic acid, ethyl ester(5.0 g.) and sodium hydroxide (0.9 g.) in ethanol (25 ml.) and water(100 ml.), stirred at room temperature. The mixture was stirred for 1.25hours and the precipitated methylthio-triazinone was collected anddried, m.p. 167-170 (3.1 g.). The filtrate was concentrated to give asecond crop (0.8 g.). Recrystallisation from aqueous ethanol affordedcolourless plates, m.p.

(d)2-Benzyl-2,5-dihydro-u-methyl-3-meth'yl-thio-5-oxoas-triazine-6-aceticacid, ethyl ester A mixture of2,4-dihydro-a-methyl-3-methylthio-5-oxoas-triazine-6-acetic acid, ethylester (20.0 g.) benzyl chloride (11.0 g.), potassium carbonate (13.0 g.)and sodium iodide (12.0 g.) in butanone (1 l.) was refluxed withstirring for 6 hours. The yellow solution was cooled and filtered toremove inorganic material, and the filtrate was concentrated to give thebenzyl derivative as an oil. This was taken up in ethyl acetate (200ml.) and the solution was filtered and concentrated to an oil whichsolidified on trituration with petroleum ether. The solid m.p. 6265(23.06 g.) was collected and dried, and then extracted with boilingcyclohexane (4X 100 ml.). The extract afforded material m.p. 72-75(16.21 g.) on cooling. Further purification by filtration through silicagel in ethyl acetate and recrystallisation from ethyl acetatecyclohexane furnished prisms, m.p. 8284.

-(e) 2-Benzyl-2,S-dihydro-a methyl-3-methylamino-5-oxo-as-triazine-6-acetic acid, ethyl ester Methylamine (ZS/30% w./v. inwater, 0.2 ml.) was added to a solution of 2-benzyl-2,5-dihydroa-methyl-3- methylthio-S-oxo-as-triazine-6-acetic acid, ethyl ester (0.5

This Example gives representative formulations containing as activeingredient 2-amino-5-methyl-7-propylimidazo[5,1-f]-as-triazin-4(3H)-onereferred in the Examples as AH 8883. This compound is used in the formof the hydrochloride which is referred to as AH 8883A.

Injection-containing 10 mg. AH 8883 per ml.

Formula Per ml. AH 8883A m 11.76 Sodium chloride mg 6.1 Water forInjections ml.... To 1.0

1 Equivalent to 10 mg. AH 8883 base.

Method of Manufacture Dissolve the AH 8883 and the sodium chloride in ofthe water for injections. When solution is complete make up to volumewith further water for injections. Filter through a suitable clarifyingtfilter.

The solution can then either be packed into 1 ml. neutral glasssnap-ring ampoules and sterilised by heating in an autoclave or byfiltration or may be prepared aseptically.

TABLETS Formula Mg [tablet Mg [tablet AH 8883 29.4 11.8 Equivalent to AH8883 b 25 10 Lactose 146. 6 120. 2 Maize starch B.P 20. 0 15. 0 Maizestarch as 5% paste. 2. 0 1. 5 Magnesium Stearate B.P 2. 0 1. 5

Final tablet Weight 200 Method of Manufacture Blend together the milledAH 8883A and Lactose. Prepare the requisite quantity of 5% Starch Pasteand add to the mixed powder and mix until a uniform damp cohesive massis formed. Granulate this mass by passing through a suitable mill orsieve to produce discrete granulates. Dry the granules in either a fluidbed drier or on trays in a hot air oven at a temperature of about 50 C.After drying pass the granules through a 30 mesh B.S. sieve to break upaggregates.

Mix together the dried granules, the Maize Starch and Magnesium Stearateand compress on a suitable tablet press. The tablets containing 30 mg.AH 8883A each weigh about 200 mg. and are 8.0 mm. in diameter, thosecontaining 10 mg. AH 8883A each weigh about 156 mg. and are 7.0 mm. indiameter.

Inhalation Aerosol Formulation Mg./metered dose 1. AH 8883 base(micronised) 0.5 2. Sorbiton trioleate 0.5 3. TrichlorofluoromethaneB.P. 23 4. Dichlorodifluoromethane B.P. 85

Method of Manufacture Disperse the micronised AH 883 base in thetrichlorofluoromethane with the Sorbitan trioleate. Fill the requisitevolume of this dispersion into suitable aerosol cans and seal by meansof a suitable metering valve. Pressurise the containers by injecting thedichlorofluoromethane through the valve.

In an alternative formula components 1, 3 and 4 are identical to 1, 3and 4 identified above but 2 is replaced by Emulsifier YN 0.01 mg.

Topical Preparation Percent w./v. 1.0

Formula AH 8883 base Cetomacrogol cream B.P.C. To 100.0

Method of Manufacture or a physiologically acceptable salt thereofwherein R and R may be the same or different and each represents ahydrogen atom or a straight or branched chain alkyl or alkenyl radicalcontaining from 1 to 6 carbon atoms or such a radical substituted by atleast one phenyl group, R is as defined for R and R or a C -C alkanoylgroup, and R and R are as defined for R and R or a C -C cycloalkyl, orphenyl group.

2. Compounds as claimed in claim 1 in which R represents hydrogen or C-C alk-anoyl; R represents hydrogen, R represents hydrogen or C -Calkyl; R represents hydrogen, or C -C :alkyl (C and R represents C -Calkyl, C -C cycloalkyl, phenyl or phenyl C -C alkyl.

3. A compound as claimed in claim 2 in which each of R R and Rrepresents hydrogen.

4. The compound of claim '1 which is 2-amino-5- methyl-7-propyl-imidazo5, l-f] -as-triazin-4 (3H) -one.

5. The compound of claim '1 which is2-amino-7-isobutyl-S-methyl-imidazo[5,l-f]-as-triazin-4 (3H)-one.

6. The compound of claim 1 which is 2-amino-7-propylimidazo 5 l-f]-as-triazin-4 3H -one.

7. The compound of claim 1 which is 2-amino-7- methyl-S-propyl-imidazo5, l-f] -as-triazin-'4 3H -one.

8. The compound of claim 1 which is 2-amino-5-methyl-7-cyclopentyl-imidazo[5,1-f]-as-triazin 4 (3H)- one.

9. The compound of claim 1 which is 2-amino-7- benzyl-S-methyl-imidazo[5, l-f] -as-triazin-4 3H) -one.

10. The compound of claim 1 which is 2-an1ino-5- methyl-7-phenyl-imidazo[5, 1-f]-as-triazin-4- (3H) -one.

11. The compound of claim 1 which is 2-amino-7-neopentyl-S-methyl-imidazo [5, l-f -as-tri-azin-4'( 3H) -one.

12. The compound of claim 1 which is 2-amino-5-methyl-7-phenethyl-imidazo 5, l-f] -as-triazin-4( 3H) -one.

13. The compound of claim 1 which is 2-amino-5,7 dimethyl-imidazo[5,1-f]-as-triazin-4(3E-I)-one.

14. The compound of claim 1 which is 2-amino-7- butyl-S-methyl-imidazo5, 1-f -as-triazin-4 3H) -one.

15. The compound of claim 1 which is N(3,4-dihydroS-methy1-4-oxo-7-propyl-imidazo[5,1-f]-as-triazin-2 yl) acetamide.

16. The compound of claim 1 which is N(2,4-dihydro5-methy1-4-oxo-7-propyl-imidazo[5,1-f]-as-triazin 2 yl butyramide.

17. The compound of claim 1 which is 2-amino-3,5-dimethyl-7-propyl-imidazo 5, l-f -as-triazin-4 3H) -one.

18. A process for the preparation of a compound of the formula:

or a physiologically acceptable salt thereof wherein R and R may be thesame or different and each represents a hydrogen atom or a straight orbranched chain alkyl or alkenyl radical containing from 1 to 6 carbonatoms or such a radical substituted by at least one phenyl group, R isas defined for R and R or a C -C alkanoyl group and R and R are asdefined for R and R or a C -C cycloalkyl, or phenyl group, whichcomprises, for the production of a compound in which R is hydrogen and RR R and R have the meanings given above, the cyclodehydration withphosphorous oxychloride or polyphosphoric acid of a compound of theformula 0 R4 0 R4 H 1 hi i NHCORa EN 1 NHCOR5 01 N N Rt 2NkN RiRzN N HzP11 VIII VIIIB.

or for the production of a compound of the formula I in which R is otherthan hydrogen, alkylating the compound of formula I above in which R ishydrogen with an alkylating agent of the formula R X wherein Xrepresents halogen or tosylate in the presence of a base and solvent toreplace the hydrogen atom by a group R as defined above.

19. A process as claimed in claim 18 in which the cyclodehydration ofthe compound of formula VIII is effected with phosphorus oxychloridewhereby debenzylation is also efiected.

'20. A process as claimed in claim 18 in which the cyclodehydration ofthe compound of formula VIIIa is carried out with polyphosphoric acid.

21. A process as claimed in claim 18 in which the compound of formulaVIIIa is made by hydrogenolysis of the compound of formula VIII.

References Cited UNITED STATES PATENTS 7/1967 Fry et al. 260-249.58/1967 Fry et al. 260-249.5 X

JOHN M. FORD, Primary Examiner

1. A A COMPOUND OF THE FORMULA I: